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Y2 MCD Cancer > clinical oncology > Flashcards

clinical oncology Flashcards

breast cancer: summarise the epidemiology of breast cancer, recall the pathological and clinical features of breast cancer, explain the pathophysiology of breast cancer, summarise the basis and role for endocrine therapies in treating breast cancer

1
Q

investigations for breast cancer

A

consultation, clinical examintation, mammography, core needle biopsy

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2
Q

proportion of cancer deaths breast cancer is responsible for, and prevalence in UK

A

1/5 (leading female cancer), with 1/8 women in UK developing it

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3
Q

why is the incidence of breast cancer rising

A

early diagnosis by self-detection (promoted by NHS)

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4
Q

why is the mortality of breast cancer falling

A

early diagnosis, chemo/radiotherapies, hormonal (endocrine) therapies

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5
Q

describe the breast and what causes its formation and when

A

very fatty organ formed during puberty due to high levels of oestrogen, as well as progesterone, from ovary; collection of ducts and glands that meet at nippe

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6
Q

what type of cancer are most malignant breast cancers

A

in clinic, breast cancer is carcinoma (tumour of luminal epithelial cells); can rarely be sarcoma (but not “clinic breast cancer”)

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7
Q

cellular organisation of mammary gland

A

luminal (inner epithelial) cells in centre, with a layer of myoepithelial cells (outer epithelial cells forming tubules; some slightly vacuolated) surround them, making contact with basement membrane; during lactation, myoepithelial cells contract to squeeze milk through lumen

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8
Q

progression of normal to malignant breast: normal

A

myoepithelial cells, attached to basement membrane, surrounding luminal epithelial cells

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9
Q

progression of normal to malignant breast: benign/in situ carcinoma

A

proliferation of luminal epithelial cells into luminal cells, forming benign carcinoma, with myoepithelial cells becoming residual

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10
Q

progression of normal to malignant breast: 3 outcomes following benign/in situ carcinoma

A

medullary carcinoma (packed full of vesicles which don’t retain morphology of tubular-like structure), unspecified infiltrating ductal carcinoma, lobular carcinoma (tumour cells retain some morphology of tubular-like structure despite loss of myoepithelial cells)

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11
Q

what carcinoma accounts for almost 80% of breast cancersm and has no special type of histological structure

A

infiltrating ductal carcinoma

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12
Q

what does immunohistochemical staining use antibodies against in invasive breast cancer

A

human oestrogen receptor (ER)

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13
Q

% of infiltrating ductal carcinomas that are ER positive

A

80% (hence ER becomes test for cancer)

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14
Q

oestrogen-related risk factors for breast cancer

A

lifetime exposure of oestrogen, age of onset of menarche, age to first full-time pregnancy, some contraceptive pills, some HRT

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15
Q

oestrogen receptor (ER) pathway causing cancer

A

oestogen passes through membrane (steroid) and binds to oestrogen receptor (associated with hsp90) in cytoplasm -> sheds hsp90 protein and binds to another oestrogen receptor -> enters nucleus -> gene expression induced by receptor dimer/oestrogen complex binding to specific DNA sequences (oestrogen response elements; within minutes of oestrogen binding) -> oestrogen-induced gene products increase cell proliferation, resulting in breast cancer

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16
Q

4 important oestrogen regulated genes and function

A

progesterone receptor (PR; sensitising cells to respond to progesterone), cyclin D1 (regulation of cell cycle), c-myc (ensure survival and not apoptosis), TGF-a (direct growth factor)

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17
Q

normal vs tumour cells responding to oestrogen

A

in normal cells, oestrogen binds to ER and causes proliferation of surrounding cells; in tumour, oestrogen drives growth of tumour cells as well

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18
Q

fraction of premenopausal women with advanced breast cancer will respond to oophorectomy (removal of ovary)

A

1/3

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19
Q

describe paradoxical nature of breast cancer in postmenopausal women, and how this happens; describe consequence

A

respond to high-dose synthetic oestrogen to cause breast tumour regression (hormonal pathways set up so if over-stimulated, receptor becomes down-regulated so lose ability to respond); would relapse with metastatic disease

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20
Q

% of breast cancers where ER is overexpressed and respond to anti-oestrogens

A

70%; some ER negative also show some response to anti-oestrogens, but not all

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21
Q

what does an increased level of ER expression indicate in women vs men

A

in women, better prognosis as treatment, but in men (rare) a worse prognosis as less effective treatment (partially driven by androgen receptor)

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22
Q

4 major treatment approaches for breast cancer

A

surgery, radiotherapy, chemotherapy, endocrine therapy

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23
Q

what is the primary therapy for breast cancer usually

A

mastectomy (removal of breast) or lumpectomy (removal of tumour and small amount of normal tissue around it)

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24
Q

what is removed in breast surgery and why

A

(sentinel) lymph nodes to see if cancer cells have spread to lymphatics

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25
Q

what is conducted following a lumpectomy (breast-conserving surgery)

A

radiotherapy

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26
Q

endocrine therapy: define adjuvant therapy

A

treatment given after primary therapy to increase the chance of long-term disease-free survival by treating any metastasis broken off from tumour mass; less common to do this before surgery as most detected before becoming too big to be operable (before had to shrink down before surgery)

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27
Q

3 levels of endocrine therapy

A

ovarian suppression in premenopausal women, blocking oestrogen production by enzymatic inhibition, inhibiting oestrogen responses (anti-oestrogen)

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28
Q

hypothalamo-pituitary-ovarian axis (only premenopausal)

A

hypothalamus -(peptide GnRH)-> pituitary -(peptides FH and LSH)-> ovary -> large quantities of oestrogens and progesterone to target cells e.g. mammary glands

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29
Q

hypothalamo-pituitary-adrenal axis (pre/post menopausal)

A

hypothalamus -(CRH)-> pituitary -(ACTH)-> adrenal gland -> androgens, which are converted to oestrogens peripherally (aromatisation), including in ovary, but especially fatty tissue e.g. mammary glands; corticosteroids and progesterone released

30
Q

hypothalamo-pituitary-prolactin/growth hormone axis

A

hypothalamus -(dopamine inhibition, TSH and GHRH)-> pituitary -> prolactin and growth hormone

31
Q

what is the major source of oestrogen biosynthesis in pre-menopausal women

A

ovary

32
Q

2 methods of ovarian ablation

A

surgical oophorectomy, ovarian irradiation (focused radiation)

33
Q

2 problems of surgical or irradiation ovarian ablation

A

morbidity, irreversibility (can’t have children)

34
Q

how can GnRH agonists achieve reversible and reliable medical ovarian ablation (can stop to allow pregnancy, then resume treatment after)

A

GnRH agonists bind to GnRH receptors in pituitary -> cell surface receptor down-regulation due to overstimulation -> suppression of LH release -> inhibition of ovarian function, including oestrogen production

35
Q

most common GnRH agonists

A

goserelin

36
Q

what inhibitors target ovarian production of oestrogens and progesterones, both from ovary and peripheral conversion of androgens from adrenal glands

A

aromatase inhibitors

37
Q

what other treatment can prevent oestrogen action

A

anti-oestrogens

38
Q

structure of oestrogens and anti-oestrogens

A

anti-oestrogens have similar structure to oestrogen, so bind to oestrogen receptor, which can’t then bind to DNA

39
Q

major anti-oestrogenic therapy which is endocrine treatment of choice for metastatic disease in postmenopausal patients

A

tamoxifen (efficacy and low incidence of side effects)

40
Q

how does tamoxifen work

A

competitive inhibitor of oestadiol binding to ER, negating stimulatory effect of oestrogen and causing cell to be held at G1

41
Q

most common side effect of tamoxifen

A

hot flushes

42
Q

how is tamoxifen given

A

as prohormone (tamoxifen citrate), which is metabolised in GI tract and liver

43
Q

what class of drugs does tamoxifen belong to

A

selective oestrogen receptor modulators (SERMs)

44
Q

advantageous oestrogenic effects of tamoxifen on bone

A

prevents osteoporosis by maintaining bone density, as antagonist in breast but agonist in bone

45
Q

advantageous oestrogenic effects of tamoxifen on CVS

A

prevents atherosclerosis and lowers low-density cholesterol, as antagonist in breast but agonist in CVS

46
Q

3 consequences of tamoxifen in uterus

A

agonist in endometrium, so causes endometrial thickening, hyperplasia and fibroids

47
Q

3 other consequences of tamoxifen in liver, cataracts and vasculature

A

increased thromboembolism in liver, increased cataracts, increased vasomotor symptoms

48
Q

3 additional drugs used in treatment of all stages of breast cancer

A

toremifene (very similar to tamoxifen), faslodex, raloxifene

49
Q

consequence of faslodex

A

oestrogen with huge side chain, purely blocking oestrogen effects causing osteoporosis and CVD

50
Q

advantage and disadvantage of raloxifene

A

antagonist of tumour growth and treats osteoporosis, but less effective in breast cancer

51
Q

what else does tamoxifen reduce the incidence of by 1/3, indicating possible use as prophylactic therapy (prevention)

A

incidence of contralateral breast cancer (new breast cancer in other breast), indicating use as prophylaxis (prevention)

52
Q

4 problems associated with using tamoxifen in prevention, hence use of other SERMs or aromatase inhibitors as preventives

A

increased incidence of endometrial cancer, stroke, DVT, cataracts

53
Q

major source of oestrogen in postmenopausal women, and where conversion occurs

A

conversion of adrenal hormones (e.g. androstenedione) to oestrogen, occuring at extra-adrenal or peripheral sites e.g. fat (mammary glands), liver and muscle

54
Q

what enzyme complex catalyses conversion of adrenal hormones to oestroen

A

aromatase enzyme complex

55
Q

what does the aromatase enzyme complex consist of

A

complex containing cytochrome P450 haem-containing protein and flavoprotein NADPH cytochrome P450 reductase

56
Q

how many steroid hydroxylations are involved in conversion of androstenedione to oestroen, and what is the prodiuct of the first hydroxylation and significance

A

3, with estrone sulphate produced in first hyroxylation which is circulated in plasma and taken up by cells and sulphate removed

57
Q

2 types of aromatase inhibitors which inhibit production of oestrogen

A

type 1 (irreversible mechanism-based suicide by binding to active site covalently), type 2 (reversible at active site so competetive)

58
Q

example of type 1 and type 2 aromatase inhibitors

A

type 1 is exemestane, type 2 is arimidex

59
Q

response rates to ER+ and PR+ breast cancer and significance

A

highest, indicating targeting PR is also useful (give progestin to over stimulate pathway and cause down-regulation of receptors)

60
Q

what is the dominant naturally occuring progestin, and property of progestins that allow use in endocrine treatment of breast and uterine cancers

A

progesterone, and they are antineoplastic

61
Q

when is progestin therapy used to treat breast cancer

A

following selective oestrogen therapy

62
Q

what is the principal progestin used for treating metastatic breast cancer

A

megestrol acetate

63
Q

describe prevalence of resistance to anti-oestrogens used to treat breast cancer

A

significant proportion of patients presenting with breast cancer, and all patients with metastatic disease, become resistant to each individual endocrine therapy (eventual relapse), even though most cases continue to demonstrate oestrogen responses and contain ER (due to mutation of ER)

64
Q

how to overcome problem of resistance to tamoxifen and other anti-oestrogens

A

continue using as they are successful, but require additional therapeutic agents/strategies for endocrine resistant, metastatic disease (e.g. inhibitors of CDKs)

65
Q

5 other risk factors of breast cancer besides those related to oestrogen exposure

A

obesity (fat converts androgen to oestrogen), diet, physical inactivity, height, medication (e.g. aspirin)

66
Q

describe criteria for screening for breast cancer (mammography)

A

all women between 50-64 once every 3 years; after cancer annual surveillance for at least 5 years to ensure disease free, so know if breast cancer has recurred or is new

67
Q

2 types of ER positive (80% of breast cancers) breast cancer, and treatment

A

luminal B/C and luminal A; treated with hormone therapy

68
Q

3 types of ER negative breast cancer, and treatment

A

basal like, ErbB2 positive, normal-like; treated with chemotherapy

69
Q

4 types of basal like ER negative breast cancer

A

metaplastic, medullary, mucinous, others

70
Q

treatment for ErbB2 positive ER negative breast cancer

A

herceptin

71
Q

biggest detection of breast cancer

A

self-detection

Y2 MCD Cancer (20 decks)

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